The matrix metalloproteinases (hereinafter abbreviated as MMP) are neutral metalloproteinases and zinc (hereinafter abbreviated as Zn.sup.2+) is essential in the active site for their activation They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and, therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue and connective tissue. At least 10 classes of MMP which differ in primary structure are identified.
As common characteristics of these enzymes, MMP
(1) have Zn.sup.2+ in the active site and the activity depends on calcium (Ca.sup.2+), PA0 (2) are secreted as an inactive proenzyme and activated outside of cells, PA0 (3) have high homology on amino acid sequence, PA0 (4) have an ability to degrade various extracellular matrix components in vivo, PA0 (5) are regulated by tissue inhibitors of metalloproteinases (TIMP) which are specific to MMP. PA0 (1) 3-(4-methylphenylsulfonyl)propionic acid isopropyl ester (122-323393), PA0 (2) 3-(4-methylphenylsulfonyl)propionic acid phenyl ester (095-006058), PA0 (3) 3-(4-methylphenylsulfonyl)propionic acid sodium salt (094-174529), PA0 (4) 3-(4-methylphenylsulfonyl)propionic acid methyl ester (122-323393), PA0 (5) 3-(4-methylphenylsulfonyl)propionic acid ethyl ester (122-323393), PA0 (6) 3-(4-methylphenylsulfonyl)propionic acid (121-009456), PA0 (7) 3-(4-ethylphenylsulfonyl)propionic acid (100-200853), PA0 (8) 3-(4-methoxyphenylsulfonyl)propionic acid phenyl ester (095-006058), PA0 (9) 3-(4-methoxyphenylsulfonyl)propionic acid, PA0 (10) 3-(4-nitrophenylsulfonyl)propionic acid methyl ester (122-323393), PA0 (11) 3-(4-nitrophenylsulfonyl)propionic acid isopropyl ester (122-323393), PA0 (12) 3-(4-nitrophenylsulfonyl)propionic acid, PA0 (13) 3-(4-aminophenylsulfonyl)propionic acid ethyl ester (115-072840), PA0 (14) 3-(4-aminophenylsulfonyl)propionic acid (085-048254), PA0 (15) 3-(4-hydroxyphenylsulfonyl)propionic acid, PA0 (16) 3-(4-hydroxyphenylsulfonyl)propionic acid phenyl ester (111-164337), PA0 (17) 3-(4-bromophenylsulfonyl)propionic acid methyl ester (066-104778), PA0 (18) 3-(4-bromophenylsulfonyl)propionic acid ethyl ester (066-104778), PA0 (19) 3-(4-bromophenylsulfonyl)propionic acid phenyl ester (095-006058), PA0 (20) 3-(4-chlorophenylsulfonyl)propionic acid methyl ester (066-104778), PA0 (21) 3-(4-chlorophenylsulfonyl)propionic acid ethyl ester (066-104778), PA0 (22) 3-(4-chlorophenylsulfonyl)propionic acid t-butyl ester (122-323393), PA0 (23) 3-(4-chlorophenylsulfonyl)propionic acid isopropyl ester (1 22-323393), PA0 (24) 3-(4-chlorophenylsulfonyl)propionic acid (101-006755), PA0 (25) 3-(4-chlorophenylsulfonyl)propionic acid phenyl ester (095-006058), PA0 (26) 3-(4-iodophenylsulfonyl)propionic acid ethyl ester (066-104778), PA0 (27) 3-(4-iodophenylsulfonyl)propionic acid methyl ester (066-104778), PA0 (28) 3-(4-acetylaminophenylsulfonyl)propionic acid methyl ester (114-014686), PA0 (29) 3-(4-acetylaminophenylsulfonyl)propionic acid ethyl ester (115-072840), PA0 (30) 3-(4-vinylphenylsulfonyl)propionic acid sodium salt (094-174529), PA0 (31) 3-(4-carboxyphenylsulfonyl)propionic acid, PA0 (32) 3-(4-cyanophenylsulfonyl)propionic acid ethyl ester, PA0 (33) 3-(4-formylphenylsulfonyl)propionic acid ethyl ester, PA0 (34) 3-(4-biphenylsulfonyl)propionic acid methyl ester (093-061046), PA0 (35) 2-amino-3-(2-methylphenylsulfonyl)propionic acid (53-14959g), PA0 (36) 2-amino-3-(3-methylphenylsulfonyl)propionic acid (53-149599), PA0 (37) 2-amino-3-(4-methylphenylsulfonyl)propionic acid (53-14959g), PA0 (38) 2-amino-3-(4-fluorophenylsulfonyl)propionic acid (53-14959g), PA0 (39) 2-t-butoxycarbonylamino-3-(4-fluorophenylsulfonyl)propionic acid (124-289512), PA0 (40) 2-amino-3-(4-chlorophenylsulfonyl)propionic acid (53-14959g), PA0 (41) 2-t-butoxycarbonylamino-3-(4-chlorophenylsulfonyl)propionic acid (124-117961), PA0 (42) 2-amino-3-(3-trifluoromethylphenylsulfonyl)propionic acid (53-14959h), PA0 (43) 2-amino-3-(4-nitrophenylsulfonyl)propionic acid (119-95106), PA0 (44) 2-amino-3-(2-nitrophenylsulfonyl)propionic acid (119-95106), PA0 (45) 2-amino-3-(4-aminophenylsulfonyl)propionic acid (119-95106), PA0 (46) 2-amino-3-(2-aminophenylsulfonyl)propionic acid (119-95106), PA0 (47) 2,2-dimethyl-3-(4-hydroxyphenylthio)propionic acid , PA0 (48) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-phenylbutylate, PA0 (49) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2-phenylbutylate, PA0 (50) 4-(2-carboxy-2-methylpropylsulfonyl)phenyl 2-phenylbutylate, PA0 (51) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-(4-methoxyphenyl)isobutylate, PA0 (52) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-(3,4-diethylphenyl)isobutyric acid, PA0 (53) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-(1,2,3,4-tetrahydro-6-naphthyl)butyrate, PA0 (54) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-(1-methyl-2-pyrrole)butyrate, PA0 (55) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2-(1-methyl-2-pyrrole)butyrate, PA0 (56) 3-(4-bromophenylthio)propionic acid, PA0 (57) N-t-butoxy-3-(4-bromophenylthio)propionamide, PA0 (58) N-t-butoxy-3-(4-biphenylthio)propionamide PA0 1) matrix metalloproteinases inhibitors containing aryl (sulfide, sulfoxide, sulfone) of the formula (I) ##STR21## PA0 R.sup.1 is hydrogen, or C1-4 alkyl, PA0 R.sup.2 is --COOR.sup.7 or --CONHOR.sup.8, PA0 R.sup.7 is hydrogen, C1-8 alkyl, phenyl, or PA0 C1-4 alkyl substituted by phenyl, --OCOR.sup.23 (in which R.sup.23 is C1-4 alkyl.), or --CONR.sup.24 R.sup.25 (in which R.sup.24 and R.sup.25, each independently, is hydrogen or C1-4 alkyl.), PA0 R.sup.8 is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl, PA0 E is --CONR.sup.9 --, --NR.sup.9 CO--, --OCO--, --COO--, --CH.sub.2 --O--, --CO--CH.sub.2 --, --(CH.sub.2).sub.2 --, --CH.dbd.CH-- or --C.ident.C-- (in which R.sup.9 is hydrogen, C1-4 alkyl, phenyl, or C1-4 alkyl substituted by phenyl. With proviso that left side of each groups is attached to J group.), PA0 J is bond or C1-8 alkylene, PA0 A is PA0 1) hydrogen, PA0 2) C1-8 alkyl, PA0 3) Ar group (Ar group is carbocyclic ring or heterocyclic ring optionally substituted by 1.about.3 of PA0 R.sup.3 and R.sup.4, each independently, is PA0 (1) hydrogen, PA0 (2) C1-8 alkyl (with proviso that one of the carbon atom in C1-8 alkyl may be replaced by a sulfur atom.), PA0 (3) --COOR.sup.19 (in which R.sup.19 is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl.), PA0 (4) Ar.sub.1 group (Ar.sub.1 group is carbocyclic ring or heterocyclic ring optionally substituted by 1.about.3 of C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy or trifluoromethyl.), PA0 (5) hydroxy, PA0 (6) --NR.sup.20 R.sup.21 (in which R.sup.20 and R.sup.21, each independently, is hydrogen, C1-4 alkyl, --COOR.sup.22 or --COR.sup.22 (in which R.sup.22 is C1-4 alkyl or benzyl.), PA0 (7) ##STR22## PA0 (8) C1-8 alkyl substituted by substituent selected from the following (a).about.(f) (with proviso that one of the carbon atom in C1-8 alkyl may be replaced by a sulfur atom.); PA0 or R.sup.3 and R.sup.4 taken together with the carbon to which they are attached, form C3-7 cycloalkyl, PA0 R.sup.5 and R.sup.6 is hydrogen or methyl, or R.sup.3 and R.sup.5 taken together, form bond, R.sup.4 and R.sup.6 are the same meanings as hereinbefore described, PA0 n is 0, 1 or 2. PA0 With proviso that: PA0 when A, J and E taken together, form phenyl, and R.sup.2 is CONHOH, then n is 1 or 2.) PA0 or non-toxic salts thereof, as active ingredient, PA0 R.sup.1 is hydrogen, or C1-4 alkyl, PA0 R.sup.2 is --COOR.sup.7 or --CONHOR.sup.8, PA0 R.sup.7 is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl, --OCOR.sup.23 (in which R.sup.23 is C1-4 alkyl.), or --CONR.sup.2 R.sup.25 (in which R.sup.24 and R.sup.25 each independently, is hydrogen or C1-4 alkyl.), PA0 R.sup.8 is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl, PA0 E is --CONR.sup.9 --, --NR.sup.9 CO--, --OCO--, --COO, --CH.sub.2 --O--, CO--CH.sub.2 --, --(CH.sub.2).sub.2 --, --CH.dbd.CH-- or --C.dbd.C-- (in which R.sup.9 is hydrogen, C1-4 alkyl, phenyl, or C1-4 alkyl substituted by phenyl. With proviso that left side of each groups is attached to J group.), J is bond or C1-8 alkylene, PA0 A is PA0 1) hydrogen, PA0 2) C1-8 alkyl, PA0 3) Ar group (Ar group is carbocyclic ring or heterocyclic ring optionally substituted by 1.about.3 of PA0 4) C1-4 alkyl substituted by hydroxy or C1-4 alkoxy, or PA0 A, J and E taken together, represents methyl, halogen, trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy, NR.sup.16 R.sup.17 (in which R.sup.18 and R.sup.17, each independently, is hydrogen, C1-4 alkyl, --COOR.sup.18 (in which R.sup.18 is C1-4 alkyl or benzyl.).), or heterocyclic ring (this heterocyclic ring may be optionally substituted by 1.about.4 of C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro, NR.sup.24 R.sup.25 (in which R.sup.24 and R.sup.25 are the same meanings as hereinbefore described.) or CONR.sup.24 R.sup.25 (in which R.sup.24 and R.sup.25 are the same meanings as hereinbefore described.).), PA0 R.sup.3 and R.sup.4, each independently, is PA0 (1) hydrogen, PA0 (2) C1-8 alkyl (with proviso that one of the carbon atom in C1-8 alkyl may be replaced by a sulfur atom.), PA0 (3) --COOR.sup.19 (in which R.sup.19 is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl.), PA0 (4) Ar.sub.1 group (Ar.sub.1 group is carbocyclic ring or heterocyclic ring optionally substituted by 1.about.3 of C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy or trifluoromethyl.), PA0 (5) hydroxy, PA0 (6) --NR.sup.20 R.sup.21 (in which R.sup.20 and R.sup.21, each independently, is hydrogen, C1-4 alkyl, --COOR.sup.22 or --COR.sup.22 (in which R.sup.22 is C1-4 alkyl or benzyl.), PA0 (7) ##STR24## PA0 (f) Ar.sub.1 group (in which Ar.sub.1 is the same meaning as hereinbefore described.) PA0 or R.sup.3 and R.sup.4 taken together with the carbon to which they are attached, form C3-7 cycloalkyl, PA0 R.sup.5 and R.sup.6 is hydrogen or methyl, or R.sup.3 and R.sup.5 taken together, form bond, R.sup.4 and R.sup.6 are the same meanings as hereinbefore described, PA0 n is 0, 1 or 2. PA0 With proviso that: PA0 (a) when A, J and E taken together, form phenyl, and R.sup.2 is CONHOH, then n is 1 or 2. PA0 (b) when R.sup.2 is --COOR.sup.7, R.sup.7 is hydrogen, C1-8 alkyl, phenyl or C1-4 alkyl substituted by phenyl, then A, J and E taken together, do not represent methyl, halogen, trifluoromethyl, nitro, cyano, hydroxy, NR.sup.16 R.sup.17 (in which R.sup.16 and R.sup.17, each independently, is hydrogen.) PA0 (c) when R.sup.2 is --COOR.sup.7, R.sup.7 is hydrogen, C1-8 alkyl, phenyl or C14 alkyl substituted by phenyl, A is hydrogen or C1-8 alkyl, J is bond or C1-8 alkyl, then E do not represent --CH.sub.2 --O--or --CH.sub.2).sub.2 O--. PA0 (d) the following (1).about.(16) compounds are excluded. PA0 (1) 3-(4-acetylaminophenylsulfonyl)propionic acid methyl ester, PA0 (2) 3-(4-acetylaminophenylsulfonyl)propionic acid ethyl ester, PA0 (3) 3-(4-vinylphenylsulfonyl)propionic acid sodium salt, PA0 (4) 3-(4-carboxyphenylsulfonyl)propionic acid, PA0 (5) 3-(4-formylphenylsulfonyl)propionic acid ethyl ester, PA0 (6) 3-(4-biphenylsulfonyl)propionic acid methyl ester, PA0 (7) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-phenylbutylate, PA0 (8) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2-phenylbutylate, PA0 (9) 4-(2-carboxy-2-methylpropylsulfonyl)phenyl 2-phenylbutylate, PA0 (10) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-(4methoxyphenyl)isobutylate, PA0 (11) 4-(2-carboxy-2methylpropylmercapto)phenyl 2-(3,4-diethylphenyl)isobutylate, PA0 (12) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-(1,2,3,4-tetraydro-6-naphthyl)butyrate, PA0 (13) 4-(2carboxy-2-methylpropylmercapto)phenyl 2-(1-methyl-2-pyrrole)butyrate, PA0 (14) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2l -methyl-2-pyrrole)butyrate, PA0 (15) N-t-butoxy-3-(4bromophenylthio)propionamide, PA0 (16) N-1-butoxy-3-(4-biphenylthio)propionamide.) PA0 (1) via an acid halide, PA0 (2) via a mixed acid anhydride, PA0 (3) using a condensing agent etc. PA0 (1) via an acid halide, PA0 (2) via a mixed acid anhydride, PA0 (3) using a condensing agent etc.
MMP inhibitors are useful for prevention and/or treatment of various diseases induced by overexpression or excess activation of MMP. Such diseases are, for example, rheumatoid diseases, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis of, invasion of or growth of tumor cells, autoimmune diseases (e.g. Crohn's disease, Sjogren's syndrome), diseases caused by vascular emigration or infiltration of leukocytes, arterialization etc.
Some compounds possessing inhibitory activity against matrix metalloproteinases are known. A sequence in the vicinity of the cleavage site of collagen (Gly-Ile-Ala-Gly or Gly-Leu-Ala-Gly) has high affinity for collagenase. Much research and development on substrate analogous matrix metalloproteinases inhibitors, which are chemically modified so as to have zinc affinity groups on a cleavage site of the substrate, has energetically been carried out [Inhibitors of matrix metalloproteinases (MMP's), Nigel RA Beeley, Phillip R J Ansell, Andrew J P Docherty et al., Curr. Opin. Ther. Patents, 4, 7-16 (1994), Current Drugs Ltd ISSN 0962-2594]. However, these substrate-analogous inhibitors might have various problems. Therefore, it is desired to obtain a non-peptide inhibitor and some compounds are reported.
For example, (1) in the specification of EP 606046, arylsulfonamide derivatives of the formula (X) ##STR4##
(wherein (a) Ar.sup.X is carbocyclic or heterocyclic aryl; R.sup.X is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R.sup.1X is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R.sup.2X is hydrogen, lower alkyl; or (b) R.sup.X and R.sup.1X taken together with the chain to which they are attached form 1,2,3,4-tetrahydro-isoquinoline, piperidine etc.; Ar.sup.X and R.sup.2X are as defined in (a); or (c) R.sup.1X and R.sup.2X taken together with the carbon to which they are attached form C3-7 cycloalkane, oxa-cyclohexane, thia-cyclohexane etc. which is unsubstituted or substituted by lower alkyl; and Ar.sup.X and R.sup.2X are as defined in (a).) are disclosed to have inhibitory activity against matrix metalloproteinase.
(2) In the specification of WO 9535276, the compounds of the formula (Y) ##STR5##
(wherein X.sup.Y is COOH, CONHOH; R.sup.1Y is .alpha.-amino acid; R.sup.2Y is Z.sup.1Y Q.sup.Y W.sup.Y ; Z.sup.1Y is hydrogen, aryl etc.; (i) Q.sup.Y W.sup.Y together form bond, (ii) Q.sup.Y is O, S, W.sup.Y is C1-20 alkyl etc., (iii) Q.sup.Y is bond, W.sup.Y is C9-20 alkyl etc., (iv) Q.sup.Y is bond, W.sup.Y is C1-8 alkyl; Y.sup.Y is SO.sub.2 ; Z.sup.Y is aryl, heteroaryl.)
are disclosed to have inhibitory activity against matrix metalloproteinase.
(3) In the specification of WO 9615096, the compounds of the formula (Z) EQU (T.sup.Z)x.sup.Z A.sup.Z -B.sup.Z -D.sup.Z E.sup.Z G.sup.Z (Z)
(wherein (T.sup.Z)x.sup.Z A.sup.Z is unsubstituted or substituted various aromatic ring or aromatic hetero ring; B.sup.Z is various aromatic ring or aromatic hetero ring; D.sup.Z is --CO--, --CH(OH)--, --CH.sub.2 -- etc.; E.sup.Z is Cn carbon chain optionally having R.sup.6Z (in which R.sup.6Z is --(CH.sub.2)v.sup.Z Z.sup.Z R.sup.8Z (in which v.sup.Z is 0, integer of 1.noteq.4; Z.sup.Z is --S--, --SO--, --SO.sub.2 -- etc.; R.sup.8Z is optionally substituted C6-10 aryl etc.)); G.sup.Z is carboxyl, alkoxycarbonyl.)
are disclosed to have inhibitory activity against matrix metalloproteinase.
(4) In the specification of WO 9509841, the compounds of the formula (E) ##STR6##
(wherein R.sup.1E is phenyl optionally having substituent etc.; R.sup.2E is hydrogen, C1-6 alkyl etc.; R.sup.3E is amino acid residue optionally having substituent; R.sup.4E is hydrogen, C1-6 alkyl etc.; R.sup.5E is hydrogen, methyl; n.sup.E is 0, 1, 2; A.sup.E is C1-6 hydrocarbon chain.)
are disclosed to have inhibitory activity against the liberation of TNF, and inhibitory activity against matrix metalloproteinase.
(5) In the specification of WO 9324449, the compounds of the formula (F) ##STR7##
(wherein RF is --CONHOH, carboxyl, esterified carboxyl etc.; R.sup.1F is hydrogen, optionally substituted alkyl, alkenyl, aryl, aralky, heteroaralkyl, heteroarylthioalkyl; R.sup.2F is optionally substituted arylthio, arylthioalkyl etc.; R.sup.3F is hydrogen, alkyl; R.sup.4F is hydrogen, alkyl; R.sup.5F is optionally substituted alkyl etc.) are disclosed to have inhibitory activity against matrix metalloproteinase.
(6) In the specification of WO 9616027, the compounds of the formula (G) ##STR8##
(wherein R.sup.1G is --CONHOH, carboxyl, alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl etc.; R.sup.2G is aryl etc.; R.sup.3G is alkyl etc.; R.sup.7G is aryl etc.; X.sup.G is --(CH.sub.2)m.sup.G Y.sup.G (CH.sub.2)n.sup.G (in which Y.sup.G is S etc.; m.sup.G, n.sup.G, p.sup.G is 0.about.4.)
are disclosed to have inhibitory activity against matrix metalloproteinase.
Also, (7) in the specification of Japanese Patent Kokai No. 4-226939 and (8) Japanese Patent Kokai No. 4-293576, each of the compound of the formula (W-1) ##STR9##
(wherein R.sup.1W-1, R.sup.2W-1 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or together form methylene, ethylene, polymethylene; R.sup.3W-1 is hydrogen, halogen, haloalkyl, C1-12 alkyl, C1-12 alkoxy etc.; R.sup.4W-1 is hydrogen, halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sup.9W-1 (in which p is 0, 1, 2, R.sup.9w-1 is hydroxy, --ONa, optionally substituted C1-12 alkyl, cycloalkyl)),
and the compounds of the formula (W-2) ##STR10##
(wherein R.sup.1W-2, R.sup.2W-2 is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, or together form methylene, ethylene, polymethylene; Ar.sup.W-2 is optionally substituted phenyl; HET.sup.W-2 is hetero ring containing nitrogen, sulfur or oxygen atom over 1 atom.) are disclosed to have inhibitory activity against elastase.
(9) In the specification of EP 0173516, the compounds of the formula (J) ##STR11##
(wherein B.sup.J is --SCH.sub.2 -- etc.; T.sup.J is oxygen etc.; R.sup.1J is optionally substituted phenyl, naphthyl by R.sup.5J, R.sup.6J, or C1-20 alkyl, alkenyl, alkynyl; R.sup.2J is hydrogen, C1-6 alkyl; R.sup.3J is hydrogen, alkyl etc.; R.sup.4J is --(CH.sub.2)p.sup.J --COOR.sup.8J (in which p.sup.J is 0.about.10; R.sup.8J is hydrogen, C1-6 alkyl.)
are disclosed to have SRS antagonistic activity or 5a-reductase inhibitory activity.
(10) In the specification of British Patent 2031408, the compounds of the formula (K) ##STR12##
(wherein R.sup.K is hydrogen, alkyl; A.sup.1K, A.sup.2K is alkylene, alkenylene; m.sup.K is 0, 1; Z.sup.K is ##STR13##
etc.; R.sup.1K, R.sup.2K is hydrogen, alkyl.)
are disclosed to have inhibitory activity against TXA.sub.2 synthetase.
(11) In the specification of British Patent 2039903, the compounds of the formula (L) ##STR14##
(wherein A.sup.L is C1-5 alkylene optionally substituted by hydroxy; E.sup.L is ##STR15##
etc.; B.sup.L is sulfur etc.; Z.sup.L is bond, C.ident.C, ##STR16##
D.sup.L is bond, C1-5 alkylene; R.sup.1L is COOR.sup.4L etc.; R.sup.4L is hydrogen, C1-12 alkyl etc.)
are disclosed to have inhibitory activity against TXA.sub.2 synthetase.
(12) In the specification of U.S. Pat. No. 4,461,905, the compounds of the formula (M) ##STR17##
(wherein A.sup.M, B.sup.M is C1-8 alkylene, alkenylene; D.sup.M is C2-10 acyl, C2-7 alkoxycarbonyl etc.; Q.sup.M is C2-7 alkoxycarbonyl etc.; X.sup.M is halogen; n.sup.M is 0, 1; Z.sup.M is ##STR18##
;EM is hydrogen, C1-6 alkyl etc.; Y.sup.M is sulfur etc.)
are disclosed to have inhibitory activity against TXA.sub.2 synthetase.
(13) In the specification of WO 865779, the compounds of the formula (N) ##STR19##
(wherein X.sup.1N is --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 --Y.sup.1N --, --Y.sup.1N --CH.sub.2 --, --COY.sup.2N --, --Y.sup.2N --CO-- (in which Y.sup.1N is oxygen etc.; Y.sup.2N is --NH--, --CH.sub.2 Y.sup.1N, --Y.sup.1N CH.sub.2 --); ##STR20##
is phenylene etc.; X.sup.2N is Y.sup.3N --Y.sup.4N -- (in which Y.sup.3N is sulfur etc.; Y.sup.4N is C1-6 alkylene); D.sup.N is --COOH, lower alkoxycarbonyl etc.; R.sup.1N is hydrogen, lower alkyl; n.sup.N is 3.about.10; A.sup.N is hydrogen, phenyl, phenoxy.)
are disclosed to have SRS antagonistic activity.
(14) in the specification of EP 181568, the compounds of the formula (P) EQU Ar.sub.1.sup.P --X.sup.P --Ar.sup.p --z.sup.P --(R.sup.P)n.sup.P (P)
(wherein Ar.sup.P is phenyl etc.; Z.sup.P is C1-10 alkylene optionally containing 0.about.2 double bonds, and it may be attached to Ar.sup.P through sulfur etc.; R.sup.P is carboxy, alkoxycarbonyl etc.; n.sup.P is 0, 1; X.sup.P is --CH.dbd.CH--, ethynylene, --COO--, --CONR.sup.1P -- etc.; Ar.sub.1.sup.P is phenyl, hetero ring containing N, S, O atom.) are disclosed to have 5-lipoxygenase inhibitory activity.
Also, the following compounds are already known. However, it is not disclosed that each compounds have inhibitory activity against matrix metalloproteinases, and it is not disclosed to suggest that these compounds have the activity thereof (the figure in the parentheses represents Chemical Abstract number.).
Compound (47).about.(49) and Compound (50).about.(55), respectively, are described in the above-mentioned (7) Japanese Patent Kokai 4-226939 and (8) Japanese Patent Kokai 4-283576.